tbuckley/cabot-search huggingface dataset:
Acidic microenvironment triggered <i>in situ</i> assembly of activatable three-arm aptamer nanoclaw for contrast-enhanced imaging and tumor growth inhibition <i>in vivo</i>
Authors: Jin Huang, Yuchen Wu, Hui He, Wenjie Ma, Jianbo Liu, Hong Cheng, Huanhuan Sun, Xiaoxiao He, Kemin Wang
Journal: Theranostics (2022)

Rationale: Static assembled multivalent DNA nanotheranostics system have encountered some bottleneck problems in cancer imaging and therapy, such as poor penetration and high immunogenicity.Herein, we proposed an acidic tumor microenvironment triggered assembly of activatable multivalent nanodevice, called "three-arm aptamer nanoclaw" (TA-aptNC), assembled from three pH-responsive aptamer-decorated DNA monomers (pH-aptDMs) to facilitate their functions of imaging and therapy. Methods:The activated TA-aptNC was constructed by acidic microenvironment triggered in situ assembly of three pH-aptDMs.Designer pH-aptDM was established based on the combination of a pH-responsive i-motif switch and an assembly module with a cell membrane anchoring aptamer ligand.Acidic microenvironment-triggered the assembly of the TA-aptNC was characterized by electrophoresis and atomic force microscopic (AFM).The binding affinity and stability of the TA-aptNC, comparing the monovalent pH-aptDM, were studied via the flow cytometry and nuclease resistance assays.Acidic microenvironment-activated contrast-enhanced tumor imaging and significantly antitumor efficiency were evaluated in vitro and in vivo.Results: At physiological pH environment, the pH-aptDMs with excellent tissue permeability exited as inactivated and monodispersed small monomer.When encountering acidic microenvironment at the tumor site, pH-responsive i-motif switch liberated from the pH-aptDMs, and the three unconstrained DNA modules (DM1, DM2 and DM3) subsequently assembled in situ into the TA-aptNC.Compared with monovalent pH-aptDMs, the spontaneously formed activatable TA-aptNC afforded 2-fold enhanced binding ability via the multivalent effect, which further facilitated the selective tumor cell uptake capability, thus enabling a contrast-enhanced tumor imaging and significantly antitumor efficiency in vivo without systemic toxicity.Conclusions: The proposed strategy offers valuable insight into excavating an endogenous stimuli-triggered assembly of multivalent nanodevice for accurate diagnosis and efficient tumor therapy.
Inflammatory endothelium-targeted and cathepsin responsive nanoparticles are effective against atherosclerosis
Authors: Fei Fang, Yinghao Ni, Hongchi Yu, Hongmei Yin, Fan Yang, Chunli Li, Denglian Sun, Tong Pei, Jia Ma, Li Deng, Huaiyi Zhang, Guixue Wang, Song Li, Yang Shen, Xiaoheng Liu
Journal: Theranostics (2022)

Rationale: Atherosclerosis is characterized by lipid accumulation, plaque formation, and artery stenosis.The pharmacological treatment is a promising therapy for atherosclerosis, but this approach faces major challenges such as targeted drug delivery, controlled release, and non-specific clearance.Methods: Based on the finding that the cathepsin k (CTSK) enzyme is enriched in atherosclerotic lesions, we constructed an integrin αvβ3 targeted and CTSK-responsive nanoparticle to control the release of rapamycin (RAP) locally.The targeted and responsive nanoparticles (T/R NPs) were engineered by the self-assembly of a targeting polymer PLGA-PEG-c(RGDfC) and a CTSK-sensitive polymer PLGA-Pep-PEG.PLGA-Pep-PEG was also modified with a pair of FRET probe to monitor the hydrolysis events.Results: Our results indicated that RAP@T/R NPs accelerated the release of RAP in response to CTSK stimulation in vitro, which significantly inhibited the phagocytosis of OxLDL and the release of cytokines by inflammatory macrophages.Additionally, T/R NPs had prolonged blood retention time and increased accumulation in the early and late stage of atherosclerosis lesions.RAP@T/R NPs significantly blocked the development of atherosclerosis and suppressed the systemic and local inflammation in ApoE -/-mice.Conclusions: RAP@T/R NPs hold a great promise as a drug delivery system for safer and more efficient therapy of atherosclerosis.
UBR5 promotes tumor immune evasion through enhancing IFN-γ-induced <i>PDL1</i> transcription in triple negative breast cancer
Authors: Bingbing Wu, Mei Song, Qun Dong, Gang Xiang, Jing Li, Xiaojing Ma, Fang Wei
Journal: Theranostics (2022)

Background:The up-regulation of PD-L1 is recognized as an adaption of cancer cells to evade immune surveillance and attack.However, the intrinsic mechanisms of the induction of PD-L1 by interferon-γ (IFN-γ) in tumor microenvironment remain incompletely characterized.Ubiquitin ligase E3 component N-recognition protein 5 (UBR5) has a critical role in tumorigenesis of triple negative breast cancer (TNBC) by triggering specific immune responses to the tumor.Dual targeting of UBR5 and PD-L1 exhibited superior therapeutic benefits in a preclinical TNBC model in short term.Methods: The regulation of UBR5 to PD-L1 upon IFN-γ stimulation was evaluated through in UBR5 deficiency, reconstitution or overexpression cell line models by quantitative PCR, immunohistochemistry and RNA-seq.The effects of PD-L1 regulation by UBR5 and double blockade of both genes were evaluated in mouse TNBC model.Luciferase reporter assay, chromatin immunoprecipitation-qPCR and bioinformatics analysis were performed to explore the transcription factors involved in the regulation of UBR5 to PD-L1.Results: E3 ubiquitin ligase UBR5 plays a key role in IFN-γ-induced PDL1 transcription in TNBC in an E3 ubiquitination activity-independent manner.RNA-seq-based transcriptomic analyses reveal that UBR5 globally affects the genes in the IFN-γ-induced signaling pathway.Through its poly adenylate binding (PABC) domain, UBR5 enhances the transactivation of PDL1 by upregulating protein kinase RNA-activated (PKR), and PKR's downstream factors including signal transducers and activators of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1).Restoration of PD-L1 expression in UBR5-deficient tumor cells recoups their malignancy in vivo, whereas CRISPR/Cas9-mediated simultaneous abrogation of UBR5 and PD-L1 expression yields synergistic therapeutic benefits than either blockade alone, with a strong impact on the tumor microenvironment.Conclusions: This study identifies a novel regulator of PDL1 transcription, elucidates the underlying molecular mechanisms and provides a strong rationale for combination cancer immunotherapies targeting UBR5 and PD-L1.
NAD<sup>+</sup>-boosting molecules suppress mast cell degranulation and anaphylactic responses in mice
Authors: Hyun-Woo Kim, Ga-Hee Ryoo, Hyun-Young Jang, So-Young Rah, Dong Hyun Lee, Do-Kyun Kim, Eun Ju Bae, Byung-Hyun Park
Journal: Theranostics (2022)

Nicotinamide adenine dinucleotide (NAD + ) acts as a cofactor for multiple biological processes.While previous research has revealed that the NAD + declines associated with aging contributes to an impairment of immune cells, its role in mast cell function, especially in response to an anaphylactic condition, has remained unexplored.We tested whether the restoration of cellular NAD + concentration by the supplementation of NAD + boosting molecules prevented mast cell degranulation and anaphylactic responses.Methods: Bone marrow derived mast cells (BMMCs) and human cord blood derived mast cells were treated with NAD + precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), and FcεRI downstream signaling was assessed.Animal models of passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) were used to investigate the effects of NAD + precursors in the anaphylactic responses of mice.Results: Treatment of murine BMMCs and human cord blood derived mast cells with NAD + precursors repressed intracellular signaling downstream of FcεRI, as well as the release of inflammatory cytokines and lipid mediators.The intraperitoneal administration of NMN or NR also markedly attenuated IgE-mediated anaphylactic responses in mouse models of PSA and PCA.These beneficial effects of NAD + precursors, however, were attenuated in mast cell-specific Sirt6 knockout mice, indicating a Sirt6 dependency for their action.Conclusion: NAD + precursors may serve as an effective therapeutic strategy that limits mast cell-mediated anaphylactic responses.
NOTCH1 signaling regulates the latent neurogenic program in adult reactive astrocytes after spinal cord injury
Authors: Zijian Tan, Shangyao Qin, Yimin Yuan, Xin Hu, Xiao Huang, Hong Liu, Yingyan Pu, Cheng He, Zhida Su
Journal: Theranostics (2022)

Background: Direct reprogramming of astrocytes into neurons opens up a new avenue for neuroregenerative medicine. However, the poor understanding of the molecular mechanisms underpinning the latent neurogenic program in astrocytes has largely restricted this strategy towards safe and effective clinical therapies. Methods: Immunocytochemistry, immunohistochemistry, western blotting, qRT-PCR, gene knockdown and fate-mapping are performed to analyze the role of NOTCH1 signaling in regulation of the latent neurogenic program in reactive astrocytes after spinal cord injury. Results: Western blotting analysis highlights that NOTCH1 is a key signaling mediating Ascl1- and Neurog2-driven astrocyte-to-neuron conversion. Inhibition of NOTCH1 signaling in cultured astrocytes by shRNA or DAPT (a NOTCH1 inhibitor) is sufficient to reprogram them into neurons by upregulating the expression of pro-neural transcription factors, including NeuroD1, NeuroD2, Pax6, Lmx1a and Lhx6. In the spinal cord of adult mouse, the expression of Notch1 is detected in resident astrocytes, which was significantly increased after spinal cord injury (SCI). Genetical knockdown of NOTCH1 signaling alone successfully triggers endogenous reactive astrocytes reprogramming into neurons in the injured adult spinal cord. Importantly, pharmacologically blocking NOTCH1 signaling with small molecule DAPT alone can also induce in situ astrocyte-to-neuron conversion after SCI. Conclusions: We identify NOTCH1 as a key common signaling pathway in reactive astrocyte that provides a barrier for cell fate conversion. This proof-of-principle study will significantly expand our molecular understanding of astroglial-lineage reprogramming and overcoming the NOTCH1 gatekeeper with small molecules may provide a transgene-free approach for in vivo chemical neuronal reprogramming with potential clinical application in neuroregeneration.
Norepinephrine acting on adventitial fibroblasts stimulates vascular smooth muscle cell proliferation via promoting small extracellular vesicle release
Authors: Chao Ye, Fen Zheng, Tao Xu, Nan Wu, Ying Tong, Xiao-Qing Xiong, Ye-Bo Zhou, Jue-Jin Wang, Qi Chen, Yue-Hua Li, Guo-Qing Zhu, Ying Han
Journal: Theranostics (2022)

Excessive sympathetic activity and norepinephrine (NE) release play crucial roles in the pathogeneses of hypertension.Sympathetic fibers innervate adventitia rather than media of arteries.However, the roles of NE in adventitial fibroblasts (AFs) are unknown.This study investigated the roles of NE in regulating AFs-derived extracellular vesicles (EVs) release and vascular smooth muscle cells (VSMCs) proliferation in hypertension.Methods: AFs and VSMCs were prepared from aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).AFs were treated with NE (10 μM) for 24 h (every 6 h, 4 times), and cultured in exosomes-depleted medium for 48 h.EVs were isolated from AFs medium with ultracentrifugation for identification and transfer to VSMCs.Results: NE promoted AFs phenotypic transformation and proliferation, which were prevented by α-receptor antagonist phentolamine rather than β-receptor antagonist propranolol.NE-treated AFs conditioned medium stimulated VSMCs proliferation, which was inhibited by either exosome inhibitor GW4869 or phentolamine.NE increased small EVs number, diameter and angiotensin converting enzyme (ACE) contents.The NE-induced EVs release was abolished by GW4869.The EVs from NE-treated AFs stimulated VSMCs proliferation, which was prevented by angiotensin II type 1 receptor antagonist losartan.The EVs from the ACE knockdown-treated AFs showed lower ACE contents, and lost their roles in stimulating VSMCs proliferation.Conclusion: NE promotes AFs-derived small EVs release and ACE transfer, and then causes VSMCs proliferation in hypertension.Intervention of AFs-derived EVs release may be potential therapeutics for excessive sympathetic activation-related vascular remodeling in hypertension.
Acellular cardiac scaffolds enriched with MSC-derived extracellular vesicles limit ventricular remodelling and exert local and systemic immunomodulation in a myocardial infarction porcine model
Authors: Marta Monguió-Tortajada, Cristina Prat-Vidal, Daina Martínez-Falguera, Albert Teis, Carolina Soler-Botija, Yvan Courageux, Micaela Munizaga-Larroudé, Miriam Moron-Font, Antoni Bayes-Genis, Francesc E. Borràs, Santiago Roura, Carolina Gálvez-Montón
Journal: Theranostics (2022)

Rationale: Extracellular vesicles (EVs) from mesenchymal stromal cell (MSC) are a potential therapy for cardiac healing after myocardial infarction (MI). Nevertheless, neither their efficient administration nor therapeutic mechanisms are fully elucidated. Here, we evaluate the preclinical efficacy of a tissue engineering approach to locally deliver porcine cardiac adipose tissue MSC-EV (cATMSC-EV) in an acute MI pig model. Methods: After MI by permanent ligation of the coronary artery, pigs (n = 24) were randomized to Untreated or treated groups with a decellularised pericardial scaffold filled with peptide hydrogel and cATMSC-EV purified by size exclusion chromatography (EV-Treated group) or buffer (Control group), placed over the post-infarcted myocardium. Results: After 30 days, cardiac MRI showed an improved cardiac function in EV-Treated animals, with significantly higher right ventricle ejection fraction (+20.8% in EV-Treated; p = 0.026), and less ventricle dilatation, indicating less myocardial remodelling. Scar size was reduced, with less fibrosis in the distal myocardium (-42.6% Col I in EV-Treated vs Untreated; p = 0.03), a 2-fold increase in vascular density (EV-Treated; p = 0.019) and less CCL2 transcription in the infarct core. EV-treated animals had less macrophage infiltration in the infarct core (-31.7% of CD163+ cells/field in EV-Treated; p = 0.026), but 5.8 times more expressing anti-inflammatory CD73 (p = 0.015). Systemically, locally delivered cATMSC-EV also triggered a systemic effect, doubling the circulating IL-1ra (p = 0.01), and reducing the PBMC rush 2d post-MI, the TNFα and GM-CSF levels at 30d post-MI, and modulating the CD73+ and CCR2+ monocyte populations, related to immunomodulation and fibrosis modulation. Conclusions: These results highlight the potential of cATMSC-EV in modulating hallmarks of ischemic injury for cardiac repair after MI.
Targeting type Iγ phosphatidylinositol phosphate kinase overcomes oxaliplatin resistance in colorectal cancer
Authors: Minhao Yu, Hao Wang, Wei Zhao, Xiaoxiao Ge, Wei Huang, Fengjuan Lin, Wenbo Tang, Ang Li, Sailiang Liu, Rong-Kun Li, Shu-Heng Jiang, Junli Xue
Journal: Theranostics (2022)

Rationale:Oxaliplatin is a widely used chemotherapy drug for advanced colorectal cancer (CRC) and its resistance is a major challenge for disease treatment.However, the molecular mechanism underlying oxaliplatin resistance remains largely elusive.Methods: An integrative analysis was performed to determine differentially expressed genes involved in oxaliplatin resistance.Loss-and gain-of-function studies were employed to investigate the roles of type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) on oxaliplatin resistance in CRC cells.Exosomes derived from CRC cell lines were assessed for PD-L1 level and the ability to promote oxaliplatin resistance.Quantitative real-time PCR, immunofluorescence, luciferase reporter assay, Western blotting and other techniques were conducted to decipher the molecular mechanism.Results: PIPKIγ was identified as a critical gene related to oxaliplatin resistance in CRC.Genetic manipulation studies revealed that PIPKIγ profoundly facilitated oxaliplatin resistance and affected the expression of DNA damage repair proteins.Mechanistically, PIPKIγ promoted the expression of the immune checkpoint molecule PD-L1 via activation of NF-κB signaling pathway.Genetic silencing of PD-L1 did not affect CRC cell proliferation but significantly sensitized CRC cells to oxaliplatin.Notably, PD-L1 was revealed to be encapsulated in the exosomes, and the addition of exosomal PD-L1 to sh-PD-L1 CRC cells restored oxaliplatin resistance.Pharmacological hijacking PIPKIγ-exosomal PD-L1 axis largely reduced oxaliplatin resistance in CRC cells.In vivo experiments showed that PD-L1 loss significantly blocked oxaliplatin resistance and the addition of PD-L1-enriched exosomes promoted tumor growth and reduced mouse survival time.Conclusion: Our findings reveal a previous unprecedented role of PIPKIγ in oxaliplatin resistance and provide a key mechanism of exosomal PD-L1 in CRC with potential therapeutics.
Image-guided drug delivery of nanotheranostics for targeted lung cancer therapy
Authors: Xiaoran Yin, Yanan Cui, Richard S Kim, Wesley R Stiles, Seung Hun Park, Haoran Wang, Li Ma, Lin Chen, Yoonji Baek, Satoshi Kashiwagi, Kai Bao, Amy Ulumben, Takeshi Fukuda, Homan Kang, Hak Soo Choi
Journal: Theranostics (2022)

Enormous efforts have been made to integrate various therapeutic interventions into multifunctional nanoplatforms, resulting in the advance of nanomedicine. Image-guided drug delivery plays a pivotal role in this field by providing specific targeting as well as image navigation for disease prognosis.
Circular RNAs modulate Hippo-YAP signaling: functional mechanisms in cancer
Authors: Javeria Qadir, Feiya Li, Burton B. Yang
Journal: Theranostics (2022)

The Hippo signaling pathway is an evolutionarily conserved network that regulates organ size and tissue homeostasis in mammals.This pathway controls various cell functions, such as growth, proliferation, survival, apoptosis, and stemness by switching 'on' or 'off' its inhibitory and/or transcriptional module, thereby regulating target gene(s) expression.Altered Hippo signaling has been implicated in various forms of cancers.Increasing evidence suggests cross-talk between the Hippo signaling pathway and non-coding RNAs, in particular circular RNAs (circRNAs).In this context, the current review presents the mechanistic interplay between the Hippo pathway and related circRNAs in various forms of cancers, along with the capabilities of these circRNAs to function either as tumor suppressors or oncogenes through miRNA sponging or protein binding mechanisms.Furthermore, we discuss the constraints and limitations in circRNA mechanistic studies while highlighting some outstanding questions regarding the roles of circRNAs associated with the Hippo-YAP pathway in cancer.Finally, we delineate the potential of these circRNAs to be employed as diagnostic and prognostic biomarkers, as well as molecular hotspots for cancer therapy.
PTBP1 knockdown promotes neural differentiation of glioblastoma cells through UNC5B receptor
Authors: Kankai Wang, Sishi Pan, Peiqi Zhao, Li Liu, Zhen Chen, Han Bao, Hao Wang, Ying Zhang, Qichuan Zhuge, Jianjing Yang
Journal: Theranostics (2022)

Rationale: Cell reprogramming technology is utilized to prevent cancer progression by transforming cells into terminally differentiated, non-proliferating states.Polypyrimidine tract binding protein 1 (PTBP1) is an RNA binding protein required for the growth of neurons and may directly transform multiple normal human cells into functioning neurons in vitro and in vivo when expressed at low levels.As a result, we identified it as a key to inhibiting cancer cell proliferation by boosting glioblastoma cell neural differentiation.Methods: Immunocytofluorescence (ICF) targeting TUJ1, MAP2, KI67, and EdU were utilized to evaluate glioblastoma cell reprogramming under PTBP1 knockdown or other conditions.PTBP1 and other target genes were detected using Western blotting and qRT-PCR.Activating protein phosphatase 2A (PP2A) and RhoA were detected using specific kits.CCK8 assays were employed to detect cell viability.Bioluminescence, immunohistofluorescence (IHF), and Kaplan-Meier survival analyses were utilized to demonstrate the in vivo reprogramming efficiency of PTBP1 knockdown in U87 murine glioblastoma model.In this study, RNA-seq technology was used to examine the intrinsic pathway.Results: The expression of TUJ1 and MAP2 neural markers, as well as the absence of KI67 and EdU proliferative markers in U251, U87, and KNS89 cells, indicated that glioblastoma cell reprogramming was successful.In vivo, U87 growth generated xenografts was substantially shrank due to PTBP1 knockdown induced neural differentiation, and these tumor-bearing mice had a prolonged survival time.Following RNA-seq, ten potential downstream genes were eliminated.Lentiviral interference and inhibitors blocking tests demonstrated that UNC5B receptor and its downstream signaling were essential in the neural differentiation process mediated by PTBP1 knockdown in glioblastoma cells.Conclusions: Our results indicate that PTBP1 knockdown promotes neural differentiation of glioblastoma cells via UNC5B receptor, consequently suppressing cancer cell proliferation in vitro and in vivo, providing a promising and feasible approach for glioblastoma treatment.
Internally inlaid SaCas9 base editors enable window specific base editing
Authors: Lurong Jiang, Jie Long, Yang Yang, Lifang Zhou, Jing Su, Fengming Qin, Wenling Tang, Rui Tao, Qiang Chen, Shaohua Yao
Journal: Theranostics (2022)

Rationale: Base editors composed of catalytic defective Cas9 and cytosine or adenosine deaminase are powerful tools to convert bases in a genome.However, the fixed and narrow editing window of current base editors has impeded their utility.To increase the scope and diversify the editing patterns is quite necessary.Methods and Results: We designed a subset of base editors derived from SaCas9 in which deaminase was inlaid into various locations of the SaCas9 protein.The resulting base editors were characterized with multiple genomic sites and were found to have distinct editing features to the N-terminal SaCas9 CBE (Sa-CBE-N).Among them, Sa-CBE-693, in which a cytosine deaminase was inserted between amino acids 693 and 694, showed an increased editing efficiency and a significantly expanded editing window ranging from bases 2-18.This feature enhanced the editing efficiency of BCL11A enhancer that contains multiple consensus bases in a 15-bp fragment.Another variant, Sa-CBE-125, displayed backward-shifted editing window, which we showed was particularly powerful in editing cytosines that were accompanied with unintended bystander cytosines at their 5' side.Additionally, these editors showed reduced Cas9 independent DNA off-target editing compared with Sa-CBE-N.Conclusion: Our inlaid base editors improved the targeting scope and diversified the editing pattern.